In 1994, there were almost 1 million deaths due to vascular disease in the United States (twice as many as from cancer and 10 times as many as from accidents). Vascular disease may affect the brain, heart, kidneys, other vital organs as well as the extremities.
The most common and serious vascular disease is atherosclerosis. Atherosclerosis is characterized by patchy subintimal thickening (atheromas) of the medium-sized arteries such as the coronary arteries, mesenteric arteries, renal arteries and carotid arteries and the large arteries such as the aorta.
Development of atherosclerotic lesions involves proliferation of cellular constituents of the wall of blood vessels in response to chemical stimuli from platelets and monocytes derived from the blood. This proliferation of cells in the vessel wall can lead to narrowing of the lumen of the vessel. In addition, atherosclerotic plaques, the focal lesions of atherosclerosis, can be sites of thrombus or clot formation, hemorrhage, or ulceration leading to interruption of the blood supply of the organ supplied by the affected blood vessel e.g., thrombus formation over an atherosclerotic plaque in a coronary artery can occlude the vessel; depriving a portion of the heart of its blood supply and thus causing ischemic death or infarction of heart muscle. Atherosclerotic plaque consists of accumulated intracellular and extracellular lipids, smooth,muscle cells, connective tissue, and giycosaminglycans. The earliest detectable lesion of atherosclerosis is the fatty streak (consisting of lipid-laden foam cells, which are macrophages that have migrated as monocytes from the circulation into the subendothelial layer of the intima), which later evolves into the fibrous plaque (consisting of intimal smooth muscle cells surrounded by connective tissue and intracellular and extracellular lipids).
The death rate from coronary artery disease (“CAD”) is significant, for example, the death rates among white men aged 25 to 34 is about 1/10,000; at age 55 to 64, it is nearly 1/100. This age relationship may be due to the time required for lesions to develop or to the duration of exposure to risk factors.
Atherosclerotic vessels are characterized by having reduced systolic expansion and abnormally rapid wave propagation. Arteriosclerotic arteries of hypertensive persons also have reduced elasticity, which is further reduced when atherosclerosis develops.
Two main hypotheses have been proposed to explain the pathogenesis of atherosclerosis: the lipid hypothesis and the chronic endothelial injury hypothesis.
The lipid hypothesis postulates that an elevation in plasma LDL levels results in penetration of LDL into the arterial wall, leading to lipid accumulation in smooth muscle cells and in macrophages (foam cells). LDL also augments smooth muscle cell hyperplasia and migration into the subintinal and intimal region in response to growth factors. LDL is modified or oxidized in this environment and is rendered more atherogenic.
The chronic endothelial injury hypothesis postulates that endothelial injury by various mechanisms produces loss of endothelium, adhesion of platelets to subendothelium, aggregation of platelets to subendothelium, aggregation of platelets, chemotaxis of monocytes and T-cell lymphocytes, and release of the platelet-derived and monocyte-derived growth factors that induce migration of smooth muscle cells from the media into the intima, where they replicate, synthesize connective tissue and proteoglycans and form a fibrous plaque. Other cells (e.g., macrophages, endothelial cells, arterial smooth muscle cells) also produce growth factors that can contribute to smooth muscle hyperplasia and extracellular matrix production.
Atherosclerotic plaque generally grow slowly and over time may produce a severe stenosis (a narrowing of the diameter of the artery) or may progress to total arterial occlusion. With time, the plaque becomes calcified. Some plaques are stable, but others, especially those rich in lipids and inflammatory cells (e.g.,macrophages) and covered by a thin fibrous cap, may undergo spontaneous fissure or rupture, exposing the plaque contents to flowing blood. These plaques are deemed to be unstable or vulnerable and are more closely associated to the onset of an acute ischemic event. The ruptured plaque stimulates thrombosis; the thrombi may embolize, rapidly occlude the lumen to precipitate heart attack or an acute ischemic syndrome, or gradually become incorporated into the plaque, contributing to its stepwise growth.
Atherosclerosis is characteristically silent until critical stenosis, thrombosis, aneurysm, or embolus supervenes. Initially, symptoms and signs reflect an inability of blood flow to the affected tissue to increase with demand (e.g., angina or exertion, intermittent claudication). Symptoms and signs commonly develop gradually as the atheroma slowly encroaches on the vessel lumen. However, when a major artery is acutely occluded, the results can be serious, such as, for example, infarction of heart muscle as described above.
Traditional therapy for prevention or inhibition of cardiovascular and cerebrovascular complications of atherosclerosis are reversing, to the extent possible, the risk factors associated with atherosclerosis such as cigarette smoking, obesity, abnormal serum levels (LDL cholesterol levels), hypertension, diabetes mellitus, hyperhomocysteinemia and possibly C. pneumoniae, infection. Hence treatment to date, is generally directed to the complications of atherosclerosis including angina pectoris, myocardial infarction, arrhythmias, heart failure, kidney failure, ischemic stroke, and peripheral arterial occlusion.
Further, vascular intervention, including angioplasty, stenting, atherectomy and grafting is often complicated by endothelial and smooth muscle cell proliferation resulting in restenosis or re-clogging of the artery. This may be due to endothelial cell injury caused by the treatment itself. Treatment of restenosis often involve a second angioplasty or bypass surgery. The drawbacks of such treatment are obvious including the risk of repeat restenosis.
For example, angioplasty involves insertion of a balloon-tipped catheter into an artery at the site of a partially obstructive atherosclerotic lesion. Inflation of the balloon is intended to rupture the intima and media and dilate the obstruction. About 20 to 30% of obstructions reocclude in just a few days or weeks. Eltchaninoff et al., Balloon Angioplasty For In-Stent Restenosis, 1998, J. Am Coll. Cardiol., 32(4): 980–984. Use of stents reduces the reocclusion rate, however a significant percentage continue to result in restenosis. The rate of stenosis after angioplasty is dependent upon a number of factors including the length of the plaque. Stenosis rates vary from 10% to 35% depending the risk factors present. Further, repeat angiography one year later reveals an apparently normal lumen in only about 30% of vessels undergoing the procedure.
In terms of the biological mechanism and characteristics leading to restenosis, accumulation of extracellular matrix containing collagen and proteoglycans in association with smooth muscle cells characterizes both the atheroma and the arterial hyperplastic lesion that lead to restenosis after balloon injury or clinical angioplasty. Some of the delay in luminal narrowing with respect to smooth muscle cell proliferation may result from the continuing elaboration of matrix materials by neointimal smooth muscle cells. Various mediators may alter matrix synthesis by smooth muscle cells in vivo. A “cascade mechanism” has been proposed for restenosis. In this model, an injurious stimulus induces expression of growth-stimulatory cytokines such as interleukin 1 and tumor necrosis factor. Libby et al., Cascade Model of Restenosis 1992, Circulation 86(6): III-47-III52.
More specifically, the acute local thrombosis, blood coagulation and/or mechanical injury appear to activate cyto gene expression by macrophages and/or smooth muscle cells within the plaque. This acute cytokine expression evokes secondary, self-sustaining and continuing autocrine and paracrine growth factor and cytokine expression by lesional cells including leukocytes. For example, both vascular endothelial and smooth muscle cells can express genes encoding both isoforms of the multipotent cytokine IL-1. Smooth muscle cells can also express the gene encoding TNF-α. Activated endothelial cells and smooth muscle cells both elaborate the B and T cell activator IL-6. IL-6 accounts for almost 4% of the newly synthesized proteins secreted by smooth muscle cells stimulated by IL-1. Human vascular wall cells also produce the monocyte chemoattractant and activator monocyte chemoattractant protein-1 (MCP-1)/JE (also known as macrophage chemoattractant and activating factor) and the monocyte differentiation and activating factor M-CSF (a macrophage colony stimulating factor).
Various therapies have been attempted to treat or prevent restenosis. For example, it has been reported that, since oxidizing metabolites may induce chain reactions that may lead to restenosis, multivitamins having antioxidant properties (30,000 IU of beta carotene, 500 mg of vitamin C and 700 IU of vitamin E) and/or probucol (500 mg) were studied. They were administered twice daily for four weeks prior and six months after angioplasty, Tardif et al., N. Engl. J. Med.: 337(6): 365–72 (1997). The antioxidant vitamins alone had no effect. Probucol did reduce the rate of restenosis after angioplasty by almost 50%. However, probucol has removed from the U.S. market for reducing HDL cholesterol levels, and causing heart rhythm disturbances which might lead to dangerous arrhythmias.
Intracoronary irradiation during angioplasty and stent implantation to reduce the instances of restenosis have likewise been studied. Limitations include, for example, handling stents filled with radioactive liquid (Re 188-radioactive rhenium). Further, studies show that this strategy may need to be tailored to stent design for proper distribution for the absorption and scattering of beta emitters. Amols et al., (1998) Circulation, 98:2024–2029.
Clearly, there remains a great need for therapies directed to the prevention and treatment of atherosclerosis, restenosis and related disorders.